Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study.

BACKGROUND: Surgical or medical castration and antiestrogenic treatment with tamoxifen are common endocrine treatments for premenopausal women with breast cancer. However, tamoxifen therapy induces high levels of plasma estradiol, with unknown long-term effects. In this study, we investigated the effect of combining estrogen suppression with the luteinizing hormone-releasing hormone agonist buserelin and estradiol receptor blockade with tamoxifen to determine whether the high estradiol levels induced by tamoxifen could be reduced and whether the antitumor effects would be better. METHODS: In a three-arm, randomized, prospective trial, from 1988 through 1995, a total of 161 premenopausal patients with advanced breast cancer were randomly assigned to treatment with buserelin, tamoxifen, or both. Patients with steroid receptor-negative tumors or with tumors of unknown receptor status who had a disease-free interval of less than 2 years were excluded. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer. Patient and tumor characteristics were well balanced among treatment groups. All P values are from two-sided tests. RESULTS: Combined treatment with buserelin and tamoxifen was superior to treatment with buserelin or tamoxifen alone by objective response rate (48%, 34%, and 28% of patients who could be evaluated, respectively; P =.11 [chi(2) test]), median progression-free survival (9.7 months, 6.3 months, and 5.6 months; P =.03), and overall survival (3.7 years, 2.5 years, and 2.9 years; P =.01). Actuarial 5-year survival percentages were 34.2% (95% confidence interval [CI] = 20.4%-48.0%), 14.9% (95% CI = 3.9%-25.9%), and 18.4% (95% CI = 7.0%-29.8%), respectively. No differences in antitumor effects were observed between single-agent treatment groups. During combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally; in contrast, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over pretreatment levels. CONCLUSION: Combined treatment with buserelin and tamoxifen was more effective and resulted in longer overall survival than treatment with either drug alone.

Maintenance chemotherapy in small-cell lung cancer: long-term results of a randomized trial. European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: The present study investigates the role of short chemotherapy (five cycles) versus prolonged (12 cycles) chemotherapy in small-cell lung cancer (SCLC). PATIENTS AND METHODS: Six hundred eighty-seven patients with SCLC were registered in a multicenter study to receive five cycles of chemotherapy consisting of cyclophosphamide 1 g/m2 on day 1, doxorubicin 45 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1, 3 and 5 (CDE), every 3 weeks. Four hundred thirty-four nonprogressing patients after five cycles of chemotherapy were randomized either to receive seven further cycles of the same chemotherapy or to follow-up. RESULTS: The response rate of 585 assessable patients was 79%, with 36% attaining a complete response. Toxicity was mainly hematologic, with 16 toxic deaths (2.4% of all eligible patients), 13 of which were due to sepsis. Median survival time from registration of all patients was 326 days (396 and 267 days for limited and extensive disease, respectively) with 3.2% of patients alive at 5 years. No difference in survival between the two arms was observed, with the same number of 5-year survivors in both arms. The patients randomized to the maintenance arm had a progression-free survival (PFS) duration approximately 2 months longer than the patients randomized to follow-up (median of 177 days v 114 days from randomization; P = .0004). Among patients with a partial response who were randomized to receive maintenance chemotherapy, 12 achieved a complete response after 12 cycles. More patients in the follow-up arm than in the maintenance arm received subsequent treatment on progression and responded more frequently to that treatment. Twelve patients developed second malignancies (seven non-small-cell lung cancers). CONCLUSION: Prolonged chemotherapy does not offer a better chance of cure than short chemotherapy (five cycles) and does not prolong survival in patients with SCLC. Short, combination chemotherapy appears to be a reasonable choice for standard treatment of SCLC and for attempts to improve the cure rate of this disease.

Two schedules of teniposide with or without cisplatin in advanced non-small-cell lung cancer: a randomized study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group.

PURPOSE: We conducted a randomized trial to investigate the value of the addition of cisplatin to teniposide (VM26) and to investigate the schedule dependence of the topoisomerase II inhibitor VM26, in advanced non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: Two hundred twenty-five NSCLC patients were randomized to receive VM26 120 mg/m2 on days 1, 3, and 5 or 360 mg/m2 on day 1 only, either as a single drug or in combination with cisplatin 80 mg/m2 on day 1. Cycles were repeated every 3 weeks. Response rates, side effects, and survival were compared according to the 2 x 2 factorial design of this study. RESULTS: The response rate of the two cisplatin-containing arms was superior to that of the two arms that contained VM26 only (22% v 6%, P < .001); progression-free survival and survival times were also longer in the cisplatin-containing arms (median, 4.3 v 2.2 months, P = .003; median 7.2 v 5.9 months, P = .008, respectively). Toxicity was significantly higher in the cisplatin-containing arms; the most frequent side effects were leukopenia, nausea and vomiting, and alopecia. The schedule of VM26 did not significantly influence the response rate, progression-free survival interval, or survival duration. However, the response rate of the 1-day administration was significantly lower than that of the 3-day administration when given as single drugs. CONCLUSION: The addition of cisplatin to VM26 improves the response rate, progression-free survival interval, and survival duration over VM26 alone, although at the cost of a significant increase in toxicity. Cisplatin should be considered as the basis for combination chemotherapies in advanced NSCLC.

Randomized trial of alternating versus sequential radiotherapy/chemotherapy in limited-disease patients with small-cell lung cancer: a European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group Study.

PURPOSE: To evaluate the effectiveness of alternating or sequential schedules of cyclophosphamide, doxorubicin, and etoposide (CDE) chemotherapy and irradiation in patients with previously untreated small-cell lung cancer (SCLC). MATERIALS AND METHODS: A total of 335 eligible patients were randomized between five courses of CDE chemotherapy followed by thoracic irradiation 50 Gy in 20 daily fractions (S) and the same total dose of chemotherapy and irradiation split into four courses of five daily fractions delivered on days 14 to 21 of the second and subsequent chemotherapy courses (A). Patients had a median age of 61 years (range, 33 to 75); 224 (66%) were male; the Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0 or 1 in 311; and 254 had weight loss less than 10%. RESULTS: The overall median survival duration was 15 months, with 62% (95% confidence interval [CI], 57% to 67%) 1-year, 25% (95% CI, 20% to 30%) 2-year, and 14% (95% CI, 10% to 18%) 3-year survival rates. There was no significant difference between the arms. The median survival time was 14 months in A and 15 months in S. One-year survival was 60% in A (95% CI, 53% to 67%) and 64% in S (95% CI, 57% to 71%); 2-year survival was 26% in A (95% CI, 19% to 33%) and 23% in S (95% CI, 16% to 30%); and 3-year survival was 12% in A (95% CI, 6% to 18%) and 15% in S (95% CI, 9% to 21%). World Health Organization (WHO) grade 3 and 4 neutropenia occurred in 90% of A and 77% of S patients (P < .001) and WHO grade 3 and 4 thrombocytopenia in 33% of A and 20% of S patients (P < .001). Rates of other acute and late toxicities were similar in both arms. Hematologic toxicity compromised treatment dose delivery; less than 50% of A patients received greater than 95% of prescribed chemotherapy and 77% their full radiation course, compared with 60% and 93% for arm S (P < .009). Local relapse was the site of first failure in 60% of all patients and 75% of these suffered an in-field relapse; no difference could be seen between the two arms. CONCLUSION: This trial failed to confirm the superiority of an alternating schedule of delivery. For this combination of chemotherapy and irradiation, hematologic toxicity compromised treatment delivery and could have contributed to the overall result. The poor rates of local control are disappointing and require intensification of the radiation therapy strategy.

Comparative study of dose escalation versus interval reduction to obtain dose-intensification of epirubicin and cyclophosphamide with granulocyte colony-stimulating factor in advanced breast cancer.

PURPOSE: A potential application of hematopoietic growth factors is to obtain an increased dose-intensity. This can be achieved by either higher doses of chemotherapy with standard intervals, or by standard doses with shorter intervals. The potential of these approaches has not been investigated systematically. PATIENTS AND METHODS: In a randomized, multicenter study, 49 advanced breast cancer patients were treated with granulocyte colony-stimulating factor (G-CSF) and either increasing doses of epirubicin and cyclophosphamide with fixed intervals (arm one) or progressively shorter intervals with fixed doses of epirubicin and cyclophosphamide (arm two). A cohort of at least six patients was studied at each interval/dose. A more intensified interval/dose was given if less than 50% of patients encountered a dose-intensity limiting criterium (DILC) in the first three courses. RESULTS: In arm one, epirubicin 140 mg/m2 and cyclophosphamide 800 mg/m2 every 21 days was too toxic. Subsequently, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 was tested with two of 10 patients encountering a DILC. All initial DILCs consisted of febrile neutropenia. In arm two, epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely with 14- and 12-day intervals. In the 10-day interval, eight of 12 patients completed the first three cycles without a DILC. In the 8-day interval, seven of eight patients encountered a DILC. Incomplete neutrophil recovery, and to a lesser extent stomatitis, were dose-limiting. CONCLUSION: In combination with G-CSF, epirubicin 120 mg/m2 and cyclophosphamide 700 mg/m2 every 21 days was feasible (projected dose-intensity, 40 mg/m2/wk and 233 mg/m2/wk, respectively). Epirubicin 75 mg/m2 and cyclophosphamide 500 mg/m2 could be administered safely every 10 days, allowing a projected dose-intensity of 52.5 mg/m2/wk and 350 mg/m2/wk, respectively.

Value of estrogenic recruitment before chemotherapy: first randomized trial in primary breast cancer.

PURPOSE: Several preclinical studies showed that short-term pretreatment of breast cancer cells with estrogens can increase the antitumor efficacy of different cytotoxic drugs. Some early clinical studies in patients with advanced breast cancer did seem to support these findings. Therefore, the efficacy of estrogenic recruitment followed by chemotherapy was compared with that of chemotherapy alone in a randomized phase III study in women with lymph node-positive primary breast cancer. PATIENTS AND METHODS: Three hundred twenty-eight patients with stage II/IIIA breast cancer who were younger than 66 years of age were randomly allocated to chemotherapy with fluorouracil, doxorubicin, and cyclophosphamide (FAC) or FAC plus pretreatment with ethinyl estradiol (EE(2)). FAC (500, 50, and 500 mg/m(2), respectively) was administered intravenously once every 4 weeks for four cycles. EE(2) (0.5 mg) was administered orally, both 24 hours and immediately preceding FAC chemotherapy. RESULTS: Patient and tumor characteristics and chemotherapy dosages were comparable in both treatment groups. Of 318 assessable patients, with a median follow-up of 6.8 years, 177 patients had a relapse and 127 died. No significant differences were observed between the two treatment groups with respect to relapse-free, local recurrence-free, and overall survival according to univariate and multivariate analyses adjusted for age, menopausal status, tumor size, grade, number of positive nodes, and steroid-receptor status. The power for the detection of an increase of 50% in the median relapse-free survival was 80%. CONCLUSION: Estrogenic recruitment of breast cancer cells before FAC chemotherapy did not influence the efficacy of adjuvant chemotherapy in stage II/IIIA breast cancer patients after a follow-up of 6.8 years.

Improved method of enrichment for immature myeloid cells from normal human bone marrow.

A method of enrichment for immature myeloid cells from normal human bone marrow has been described. The method is based on 4 consecutive steps: 1. Density cut centrifugation. After centrifugation all cells above the pellet were collected. This suspension contained 93% of the originally present myeloblasts and promyelocytes. The majority of normoblasts and granulocytes was found in the pellet. 2. Nylon wool filtration. This procedure was performed to remove the majority (87%) of the monocytes. Recovery of myeloblasts and promyelocytes after filtration was 74%. 3. Centrifugation on a continuous density gradient. This procedure resulted in an additional purification of the myeloblasts and promyelocytes within a specific fraction. By centrifugation the concentration of myeloblasts and promyelocytes was increased from 19% to 38%. 4. Velocity sedimentation at 1 g. This technique produced a 82% pure immature myeloid cell suspension, comprising 57% myeloblasts and promyelocytes. All figures are the mean of 10 experiments.

Tamoxifen as sole therapy for primary breast cancer in the elderly patient.

In a retrospective study the data concerning 40 patients, with primary operable breast cancer were analysed. The mean follow-up of the patient group was 29 months. All patients received tamoxifen only. 17 (43%) reached remission and there was stable disease in 16 (40%). 7 (18%) showed progression, although they have had stable disease for at least 18 months. There were 1 local, 1 distant and 5 local plus distant progressions. 3 patients required salvage mastectomy. The mean progression-free interval was 33 months. Death was attributable to breast carcinoma in only 6 patients (15%). The 3-year survival was 47.2%. We conclude that primary treatment with tamoxifen as a sole therapy is acceptable in operable breast carcinoma for those patients for whom surgery is contraindicated or who refuse surgery.

Phase II trial of cisplatin for adenocarcinoma of unknown primary site. IKZ/IKO Clinical Research Group.

The activity of cisplatin against advanced metastatic adenocarcinoma of unknown primary site (ACUP) was evaluated in 21 patients. Cisplatin (100 mg/m2) was given as a 4-h continuous infusion every 3 weeks, with appropriate fluids and diuretics. The overall response rate was 19% with 1 complete remission for 12 months and 3 partial remissions lasting from 4 to 7 months. 7 patients achieved stable disease and in 9 patients the disease was progressive. The median duration of response was 6.5 months. The median survival 7.5 months. The median survival of the total patient group was 5 months (range 1-18 months). Toxicity comprised mainly nausea and vomiting, mild creatinine elevation and leukocytopenia. Slight ototoxicity was observed in 6 patients.

Standard versus alternating non-cross-resistant chemotherapy in extensive small cell lung cancer: an EORTC Phase III trial.

Alternating chemotherapy for small cell lung cancer has been tested in several studies. Some have shown positive results that have not been confirmed in other studies. In all of the studies, however, the degree of non-cross-resistance in the regimens was questionable. The EORTC Lung Cancer Study Group developed two equipotent regimens: (i) standard (CDE)-cyclophosphamide, doxorubicin, etoposide; (ii) (VIMP)-vincristine, carboplatin, ifosfamide, mesna, both non-cross-resistance. These two combinations were alternated and compared with the standard chemotherapy regimen in a group of 143 patients with extensive small cell lung cancer. Median survival was 7.6 months in the standard arm and 8.7 in the alternating arm (P = 0.243). Median time to progression was 5.8 and 6.4 months, respectively (P = 0.166). Median response duration was 7.0 and 6.8 months (P = 0.221). The use of two alternating regimens with a proven degree of non-cross-resistance did not result in any improvement in survival in patients with extensive small cell lung cancer.

Comparison of two carboplatin-containing regimens with standard chemotherapy for small cell lung cancer in a randomised phase II study. The EORTC Lung Cancer Cooperative group.

The EORTC Lung Cancer Cooperative group performed a randomised phase II study in patients with small cell lung cancer comparing the standard cyclophosphamide/doxorubicin/etoposide (CDE) regimen with two regimens containing the new and active cisplatin derivative, carboplatin, 400 mg/m2 in combination with ifosfamide, a drug without important myelotoxicity, at a dose of 5 g/m2 (IMP) or the non-myelotoxic drug vincristine twice 2 mg (VP). Of 178 evaluable patients, 63 received CDE [30 limited disease (LD), 33 extensive disease (ED)], 55 received IMP (22 LD, 33 ED) and 60 (26 LD, 34 ED) were treated with VP. The response duration was not statistically different: CDE 31 weeks, IMP 29 weeks and VP 21 weeks. The time to progression after CEE was 28 weeks, IMP 24 weeks and VP 17 weeks. This was significantly shorter after VP than after CDE (P = 0.017). The 60% response rate of the VP combination was low compared with CDE (83%) and IMP (77%). Toxicity of all three regimens was acceptable, and dose reduction for myelosuppression was necessary in only a minority of the patients. We conclude from this study that the combination of carboplatin, at the maximally tolerated dose of 400 mg/m2, in combination with ifosfamide 5 g/m2, is an active regimen with efficacy comparable with the standard CDE regimen.

Role of recombinant interferon-gamma maintenance in responding patients with small cell lung cancer. A randomised phase III study of the EORTC Lung Cancer Cooperative Group.

This study was undertaken to determine if recombinant interferon-gamma (rIFN-gamma) given every other day as maintenance therapy could prolong the survival of patients with small cell lung cancer (SCLC) who achieved a complete or nearly-complete response to induction therapy. A secondary endpoint was to assess the toxicity of alternate day doses of this treatment. One hundred and seventy seven patients in complete or nearly-complete response following chemotherapy with or without thoracic radiotherapy were studied. Patients were randomised to receive either rIFN-gamma 4 million units (0.2 mg) subcutaneously every other day for 4 months or observation. One hundred and twenty of the 127 registered patients were eligible; 59 patients received IFN and 61 patients without maintenance therapy were followed. Alternate day IFN was reasonably well tolerated by the majority of patients, but in 12% substantial non-haematological toxicity (including flu-like syndrome) occurred. One of 3 patients with pneumonitis died after having received 3.6 mg IFN. The median survival time from the date of randomisation was 8.9 months for the IFN arm and 9.9 months for the observation arm. rIFN-gamma at the dose and schedule used in this study failed to prolong response duration and survival in SCLC patients in complete or nearly-complete response. The toxicity seen with every other day doses of IFN was less than that reported with daily dosing. The hypothesis that this agent may increase the deleterious effects of radiation on normal lung tissue was supported by the development of pneumonitis in 3 cases of whom 1 had a fatal outcome. The results do not warrant further studies with rIFN-gamma on maintaining response in SCLC.

Fluorouracil continuous infusion plus alfa interferon plus oral folinic acid in advanced colorectal cancer.

Several reports on fluorouracil (5-FU) and alfa interferon (IFN-alpha) combination therapy in patients with advanced colorectal cancer have been published. In our study high-dose continuous infusion 5-FU (60 mg/kg per 48 hours), oral folinic acid (FA) (8 x 90 mg during 5-FU), and IFN-alpha three times weekly were combined. Because the addition of IFN-alpha has not been tested before, and serious toxicity of 5-FU plus IFN-alpha therapy has been reported, the IFN-alpha dose was escalated from 3 to 10 million units (MU)/dose in the first 11 patients. Grade 3 toxicity was noted in four patients, and consisted mainly of oral mucositis. No grade 4 toxicity occurred. Three partial responses were noted. Preliminary results of a phase II study, in which all patients received IFN-alpha at 10 MU/dose, show grade 3 and 4 toxicities in 24% and 4% of patients, respectively. This compares favorably with other trials in which 5-FU and IFN-alpha was used without FA.

A multicenter phase II trial of cisplatin and oral etoposide (VP-16) in inoperable non-small-cell lung cancer.

Sixty patients with inoperable non-small-cell lung cancer (NSCLC) were entered into a phase II study that tested the combination of cisplatin (80 mg/m2, day, etoposide intravenously (IV) (100 mg, days 1 and etoposide orally (200 mg/m2, days 3 and 5). The regimen was repeated every 28 days for six courses, after which patients were allowed to receive additional treatment at the discretion of their physician. Overall objective response rate in 51 evaluable patients was 69% (95% confidence interval: range, 56% to 81%), with 16% sustaining complete remission (CR), 53% partial remission (PR), 17% stable disease (SD), and 14% progressive disease (PD). CR was pathologically confirmed by bronchoscopy and biopsy. One patient with a clinical PR underwent surgery and was shown to have a pathologic CR. Median survival of all evaluable patients was 52 weeks, greater than 75 weeks for CR patients, 52 weeks for PR patients, 42 weeks for SD patients, and 13 weeks for PD patients. Eleven patients (21.5%) developed CNS metastases, which resulted in the deaths of ten. Survival was significantly correlated with extent of disease, performance status, and albumin level, but not with histology or weight loss. Tumor response was significantly correlated only with histology (squamous-cell and large-cell undifferentiated carcinoma greater than adenocarcinoma). Side effects were nausea, vomiting, anorexia, alopecia, bone marrow suppression, and nephrotoxicity. One patient died from leukopenia and sepsis. Pharmacokinetic studies in ten patients showed the continuous presence of etoposide in plasma for six days at a level of at least 220 to 480 ng/mL. In order to investigate whether this very effective combination of cisplatin and etoposide can prolong survival in NSCLC, it will be tested as preoperative chemotherapy in a randomized trial in operable patients with T1N1 and T2N0-1 disease.

Incorporation of nucleic acid and protein precursors in enriched populations of proliferating normal and leukemic cells.

Nucleic acid and protein synthesis was determined in immature myeloid cells isolated from seven normal bone marrow samples and compared to blasts from nine patients with fullblown acute non-lymphocytic leukemia. Samples obtained from normal bone marrow contained a mean of 82% immature myeloid cells with 29.9% S-phase cells. These cells incorporated [3H]thymidine with a mean of 17,500 counts/min [3H]uridine with a mean of 24,000 counts/min and [3H]leucine with a mean of 2100 counts/min per 0.2 x 10(6) cells. Leukemic bone marrow cells could be separated in fractions with different proliferative activities. Leukemic samples with a mean of 3.6% S-phase cells incorporated [3H]thymidine with a mean of 1100 counts/min, [3H]uridine with a mean of 15,700 counts/min and ]3H]leucine with a mean of 2600 counts/min per 0.2 x 10(6) cells. For leukemic samples with a mean of 30.6% S-phase cells these values were: [3H]thymidine 22,200 counts/min, [3H]uridine 49,700 counts/min and [3H]leucine 6700 counts min per 0.2 x 10(6) cells. The incorporation studies were carried out for the first time in normal and leukemic cells with a comparable proliferative activity. Non-lymphocytic leukemic blastic cells showed a two-fold increase in RNA synthesis and a three-fold increase in protein synthesis compared to enriched samples of normal early myeloid cells with the same proliferative activity.

Teniposide for meningeal carcinomatosis of small cell lung cancer.

A female patient with small cell lung cancer and extensive bone marrow metastases achieved a complete response after combination chemotherapy including etoposide. During maintenance therapy meningeal carcinomatosis was diagnosed. After intravenous administration of teniposide she improved dramatically during 3 months.

Alpha-interferon in combination with 5-fluorouracil and leucovorin in metastatic colorectal cancer: a phase I study.

A high rate of response to 5-fluorouracil (5FU) and alpha-interferon (alpha IFN) combination therapy has been reported in metastatic colorectal cancer patients. Therefore, designed a trial of high-dose continuous-infusion 5FU, oral leucovorin (LV), and alpha IFN in this group of patients. Because this combination has not previously been tested and severe toxicity has been reported for 5FU and alpha IFN combination therapy, we conducted a phase I trial in which 11 patients presenting with previously untreated metastatic colorectal cancer were treated with escalating doses of alpha IFN together with fixed doses of 5FU and LV. WHO grade III toxicity consisting mainly of oral mucositis was noted in four patients. No grade IV toxicity occurred. Although alpha IFN may enhance the toxicity of 5FU, the toxicity of this regimen remained manageable. Three partial responses were noted.

High-dose 5-fluorouracil and leucovorin as second-line chemotherapy in patients with platinum-resistant epithelial ovarian cancer.

A total of 14 patients with platinum-resistant advanced epithelial ovarian cancer were treated with a continuous infusion of high-dose 5-fluorouracil (5-FU, 1200 mg/m2 per day) for 2 consecutive days weekly for 4 weeks and, thereafter, every 2 weeks in combination with a push injection of folinic acid (20 mg/m2) given just before 5-FU and after 24 h. No objective response was documented, and only five patients showed stable disease. The median survival was 6.5 months. There was minimal toxicity. This schedule of 5-FU in combination with folinic acid is not effective as second-line chemotherapy in advanced ovarian cancer.

Phase II trial of 5-fluorouracil, adriamycin and cisplatin (FAP) in advanced gastric cancer.

Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m2 IV on days 1-5, adriamycin 50 mg/m2 IV on day 1, cisplatin 20 mg/m2 IV on days 1-5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patient showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2 X 10(9)/l (range 0.7-4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).

Double alternate modulation of high-dose 5-Fluorouracil by interferon-alpha-2b and phosphonacetyl-L-aspartic Acid in patients with advanced colorectal-cancer.

We conducted a multicenter phase II trial in patients with advanced colorectal cancer to investigate the antitumor efficacy of double alternate modulation of high-dose infusional 5-fluorouracil (5FU) (60 mg/kg/48 h = 2400 mg/m(2)/48 h) by interferon alpha-2b (IFN alpha) (10 MU/dose s.c. prior to and halfway 5FU, uneven cycles) and phosphonacetyl-L-aspartic acid (PALA) (250 mg/m(2) i.v. 24 h before 5FU, even cycles). Cycles were given weekly for 4 weeks and once every 2 weeks thereafter. Twenty one patients with progressive or symptomatic disease were treated ambulatory. Two patients (10%, 95% confidence interval 1-30%) achieved a partial response. Therefore, this schedule of double alternate modulation of 5FU is unlikely to be superior to single modulation of 5FU in patients with advanced colorectal cancer. Since no grade III/IV toxicity (WHO) occurred during 251 cycles, which is in contrast to our previous studies using the same 5FU schedule, it might be possible that alternate modulation allows more intense 5FU schedules compared to single or double modulation schedules.